6-(2-imidazolinylamino) quinolines useful as alpha-2 adrenoceptor agonists

Abstract

The subject invention relates to compounds having the structure: ##STR1## as defined in the claims, and to pharmaceutical compositions containing such compounds, and the use of such compounds for preventing or treating of disorders modulated by alpha-2 adrenoceptors.

Claims

1. A compound having the following structure: ##STR12## wherein: (a) R.sub.4 is selected from the group consisting of hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; cycloalkyl; cycloalkenyl; methyl monosubstituted with hydroxy, thiol or amino; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; amino; unsubstituted amide; amido, unsubstituted or substituted with alkanyl or alkenyl having from 1 to about 3 carbon atoms; halo; unsubstituted sulfoxide; unsubstituted sulfonyl; and cyano;

(b) R.sub.5 is unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms;

(c) R.sub.7 is selected from hydrogen; unsubstituted C.sub.1 -C.sub.3 alkanyl or alkenyl; hydroxy, thiol or amino; halo; and cyano;

(d) R.sub.8 is selected from the group consisting of hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; and halo.

2. A compound according to claim 1 wherein R.sub.7 is hydrogen.

3. The compound of claim 2 wherein R.sub.4 is selected from the group consisting of hydrogen, unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms, cycloalkyl, cycloalkenyl, unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; cyano; amino; and halo.

4. The compound of claim 3 wherein R.sub.5 is alkanyl, and R.sub.8 is selected from the group consisting of methyl, methoxy, chloro and bromo.

5. The compound of claim 4 wherein R.sub.4 is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano, chloro and fluoro.

6. The compound of claim 5 wherein R.sub.5 is methyl.

7. The compound of claim 2 wherein both R.sub.5 and R.sub.8 are methyl.

8. The compound of claim 7 wherein R.sub.4 is selected from the group consisting of hydrogen, cyano and fluoro.

9. The compound of claim 8 wherein R.sub.4 is hydrogen.

10. The compound of claim 1 wherein:

R.sub.4 is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano, chloro and fluoro;

R.sub.5 is methyl, ethyl or cyclopropyl;

R.sub.7 is methyl, chloro, fluoro or bromo; and

R.sub.8 is hydrogen, methyl, chloro or bromo.

11. The compound of claim 10 wherein R.sub.4 and R.sub.8 are hydrogen, and R.sub.5 and R.sub.7 are methyl.

12. A pharmaceutical composition comprising:

(a) a safe and effective amount of a compound of any of claims 1, 2, 8, 9, 10 or 11 and

(b) a pharmaceutically-acceptable carrier.

13. A pharmaceutical composition according to claim 12 further comprising one or more actives chosen from the group consisting of an antihistamine, antitussive, mast cell stabilizer, leukotriene antagonist, expectorant/mucolytic, antioxidant or radical inhibitor, steroid, bronchodilator, antiviral, analgesic, antiinflammatory, gastrointestinal and ocular active.

14. A pharmaceutical composition according to claim 12 further comprising an antihistamine.

15. A pharmaceutical composition according to claim 12 further comprising an antiinflammatory.

16. A method for preventing or treating a disorder modulated by alpha-2 adrenoreceptors, by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoreceptor agonist compound according to claim 1.

17. A method for preventing or treating a disorder modulated by alpha-2 adrenoreceptors, wherein the disorder is chosen from the groups comprising, nasal congestion, otitis media, sinusitis, asthma, pain, migraine, substance abuse and addiction, gastrointestinal disorder, ulcer, stomach hyperacidity, benign prostatic hypertrophy, by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoreceptor agonist compound according to claim 1.

18. A method of treating or preventing nasal congestion by administering to a mammal in need of such treatment a safe and effective amount of a compound according to claim 1.

19. A method of treating or preventing nasal congestion by administering to a mammal in need of such treatment a safe and effective amount of a compound according to claims of any of claims 1, 8, 9 or 11.

20. The method of claim 17, wherein the disorder is otitis media.

21. The method of claim 17, wherein the disorder is sinusitis.

22. A method for preventing or treating a respiratory disorder, wherein the disorder is chosen from the group comprising cough, chronic obstructive pulmonary disease and asthma, by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to claim 1.

23. A method for preventing or treating a respiratory disorder according to claim 22, wherein the disorder is asthma.

24. A method for preventing or treating disorders mediated by sympathetic activity and modulated by alpha-2 adrenoreceptors by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoreceptor agonist compound according to claim 1.

25. A method of treating a disorder according to claim 24, wherein the disorder is chosen from the group comprising benign prostatic hypertrophy, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.

26. The method of claim 25, wherein the disorder is heart failure.

27. A method for preventing or treating an ocular disorder modulated by alpha-2 adrenoreceptors, by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to claim 1.

28. A method for preventing or treating an ocular disorder according to claim 27 wherein the disorder is chosen from the group comprising ocular hypertension, hyperemia, conjunctivitis, and uveitis and glaucoma.

29. A method for preventing or treating an ocular hypertensive disorder according to claim 28 wherein the disorder is glaucoma.

30. A method for preventing or treating a gastrointestinal disorder modulated by alpha-2 adrenoreceptors by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoreceptor agonist compound according to claim 1.

31. A method for preventing or treating a gastrointestinal disorder, according to claim 30, wherein the disorder is chosen from the group comprising diarrhea and irritable bowel syndrome.

32. A method for preventing or treating a gastrointestinal disorder, according to claim 31, wherein the disorder is diarrhea.

33. A method for preventing or treating migraine by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to claim 1.

34. A method for preventing or treating pain by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to claim 1.

35. A method for treating substance abuse by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to claim 1.

36. A compound having the following structure: ##STR13## wherein: (a) R.sub.4 is selected from the group consisting of hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; cycloalkyl; cycloalkenyl; methyl monosubstituted with hydroxy, thiol or amino; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; amino; unsubstituted amide; amido, unsubstituted or substituted with alkanyl or alkenyl having from 1 to about 3 carbon atoms; halo; unsubstituted sulfoxide; unsubstituted sulfonyl; and cyano;

(b) R.sub.5 is unsubstitutod alkanyl or alkenyl having from 1 to about 3 carbon atoms;

(c) R.sub.7 is selected from hydrogen; unsubstituted C.sub.1 -C.sub.3 alkanyl or alkenyl; hydroxy, thiol or amino; halo; and cyano;

(d) R.sub.8 is selected from the group consisting of hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; and halo;

(e) provided that both R.sub.7 and R.sub.8 are not hydrogen.